Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Lung function and atherosclerosis: a cross-sectional study of multimorbidity in rural Uganda.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality. In high-income settings, the presence of cardiovascular disease among people with COPD increases mortality and complicates longitudinal disease management. An estimated 26 million people are living with COPD in sub-Saharan Africa, where risk factors for co-occurring pulmonary and cardiovascular disease may differ from high-income settings but remain uncharacterized. As non-communicable diseases have become the leading cause of death in sub-Saharan Africa, defining multimorbidity in this setting is critical to inform the required scale-up of existing healthcare infrastructure. METHODS: We measured lung function and carotid intima media thickness (cIMT) among participants in the UGANDAC Study. Study participants were over 40 years old and equally divided into people living with HIV (PLWH) and an age- and sex-similar, HIV-uninfected control population. We fit multivariable linear regression models to characterize the relationship between lung function (forced expiratory volume in one second, FEV1) and pre-clinical atherosclerosis (cIMT), and evaluated for effect modification by age, sex, smoking history, HIV, and socioeconomic status. RESULTS: Of 265 participants, median age was 52 years, 125 (47%) were women, and 140 (53%) were PLWH. Most participants who met criteria for COPD were PLWH (13/17, 76%). Median cIMT was 0.67 mm (IQR: 0.60 to 0.74), which did not differ by HIV serostatus. In models adjusted for age, sex, socioeconomic status, smoking, and HIV, lower FEV1 was associated with increased cIMT (ß = 0.006 per 200 mL FEV1 decrease; 95% CI 0.002 to 0.011, p = 0.01). There was no evidence that age, sex, HIV serostatus, smoking, or socioeconomic status modified the relationship between FEV1 and cIMT. CONCLUSIONS: Impaired lung function was associated with increased cIMT, a measure of pre-clinical atherosclerosis, among adults with and without HIV in rural Uganda. Future work should explore how co-occurring lung and cardiovascular disease might share risk factors and contribute to health outcomes in sub-Saharan Africa.

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry.

BACKGROUND AND AIMS: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). METHODS: CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. RESULTS: The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ±â€¯15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ±â€¯68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ±â€¯11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. CONCLUSIONS: With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.

HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana.

BACKGROUND: Untreated HIV infection is associated with increased biomarkers of endothelial dysfunction. However, the predictors and degree of endothelial dysfunction among virally suppressed HIV-infected adults on long-term antiretroviral therapy (ART) have not been well studied in sub-Saharan Africa (SSA). METHODS: We enrolled 112 HIV-infected adults with virological suppression on long-term ART and 84 HIV-uninfected controls in Botswana. We measured plasma levels of markers of endothelial injury [soluble vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-selectin] and plasma levels of biomarkers of inflammation [interleukin 6 (IL-6)] and monocyte activation (sCD163). Baseline traditional cardiovascular disease (CVD) risk factors and bilateral common carotid intima-media thickness (cIMT) were also available for all participants. We assessed whether HIV status (despite virological suppression on ART) was associated with biomarkers of endothelial dysfunction after controlling for traditional CVD risk factors in linear regression models. We additionally assessed the association between IL-6, sCD163 and cIMT with endothelial dysfunction in separate multivariate linear regression models, controlling for cIMT, among virally suppressed HIV-infected participants only. RESULTS: In multivariate analysis, HIV infection was significantly associated with increased VCAM-1 (p < 0.01) and ICAM-1 (p = 0.03) but not E-selectin (p = 0.74) levels. Within the HIV-positive group, higher sCD163 levels were associated with decreased ICAM-1 and E-selectin (p < 0.01 and p = 0.01, respectively) but not VCAM-1 (p = 0.13) levels. IL-6 was not associated with any of the biomarkers of endothelial dysfunction. CONCLUSION: HIV disease was associated with biomarkers of endothelial dysfunction among virally suppressed adults in Botswana on long-term ART after controlling for traditional CVD risk factors. Future work should explore the clinical impact of persistent endothelial dysfunction following long-term HIV viral suppression on the risk of CVD clinical endpoints among HIV-infected patients in this setting.

Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH™ patient registry.

BACKGROUND AND AIMS: Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients. METHODS: We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance. RESULTS: In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90). CONCLUSIONS: In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.

US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry.

BACKGROUND: Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. METHODS AND RESULTS: We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). CONCLUSIONS: FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (ß = 0.001; p = 0.02) and atherosclerosis risk factors (ß = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). CONCLUSIONS: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.

BACKGROUND: Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. DESIGN: The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. SUMMARY: The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy.

Familial hypercholesterolemia (FH), an autosomal-dominant inherited disorder, can occur in either the heterozygous (HeFH) or homozygous (HoFH) state, and is characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C). Although potent statins and maximally tolerated lipid-lowering therapy (LLT) have greatly reduced the risk of premature coronary heart disease (CHD) and death, all patients with HoFH and many with severe HeFH remain far from treatment goals and are thus at risk of cardiovascular disease. LDL apheresis is the treatment of choice for these patients but remains underutilized. No formal studies or epidemiologic data have estimated the prevalence of HoFH. An HeFH prevalence of 1:500 and a simplified Hardy-Weinberg equilibrium model was used to determine the probability of finding HoFH as 1:1 million in the general population. A US population of approximately 314.8 million was used to determine the number of cases of HoFH and HeFH. The following key parameters were used to estimate the prevalence of severe HeFH: baseline pretreatment LDL-C level and distribution of patients with FH, posttreatment LDL-C level and distribution after maximally tolerated LLT, and baseline percentage of patients with HeFH who have CHD. We assumed an HeFH prevalence of 1:500 and used statistics for a Gaussian distribution after the posttreatment means and standard deviations of LDL-C levels in patients with HeFH receiving maximally tolerated LLT, as has been documented by data from clinical trials and cross-sectional studies. These estimates do not include the statin-intolerant population. The objective of this analysis was to determine the prevalence of the US population with severe HeFH with or without CHD who still will be eligible for LDL apheresis despite maximally tolerated LLT. We estimated that there are 315 US patients with HoFH and 650,000 with HeFH. The estimated prevalence of the severe HeFH population eligible for apheresis is approximately 1:20,000 (range, 1:11,700-1:62,500). This estimate suggests that, based on the efficacy of maximally tolerated LLT and CHD status, approximately 15,000 (approximately 2.4%) of the 625,000 patients with HeFH who are maximally treated will still be eligible for LDL apheresis.

Increased skeletal muscle phosphocreatine recovery after sub-maximal exercise is associated with increased carotid intima-media thickness.

BACKGROUND: The association between skeletal muscle mitochondrial function and CVD risk in healthy subjects is unknown. METHODS: Forty subjects were evaluated for CVD risk with lipid profile, oral glucose tolerance test and measurement of carotid intima-media thickness (cIMT). Skeletal muscle mitochondrial function was determined by phosphocreatine recovery after sub-maximal exercise with (31)Phosphorous-MRS and represented as τPCr. RESULTS: τPCr was positively associated with age (r=+0.41; P=0.009) and cIMT (r=+0.50; P=0.001) on univariate analyses. In multivariate regression analysis controlling for age, the association between τPCr and cIMT remained significant (ß=0.003; P=0.03). This association remained significant after controlling for traditional risk factors for CVD including age, gender, tobacco use, BMI, blood pressure, cholesterol and fasting glucose in a combined model (ß=0.003; P=0.04; R(2)=0.53; P=0.008 for overall model). CONCLUSIONS: These data suggest a novel association between skeletal muscle τPCr and increased cIMT, independent of age or traditional CVD risk factors.

Familial hypercholesterolemia: current treatment options and patient selection for low-density lipoprotein apheresis.

Options for treatment of severe heterozygous and homozygous familial hypercholesterolemia prior to the statin era were limited by significant side effects and morbidity. The advent of both the statins and technology for the selective removal of LDL via apheresis have revolutionized management but challenges remain.

Reduced growth hormone secretion is associated with increased carotid intima-media thickness in obesity.

CONTEXT: Obesity is associated with reduced GH. OBJECTIVE: The aim of the study was to determine whether reduced GH is associated with increased carotid intima-media thickness (cIMT) in obesity. DESIGN: A total of 102 normal-weight and obese men and women without known hypopituitarism were studied. Subjects underwent GH stimulation testing with GHRH-arginine. Lipid profile, inflammatory markers, oral glucose tolerance test, abdominal computed tomography, dual-energy x-ray absorptiometry, and cIMT were measured. Relative GH deficiency was defined as peak GH of 4.2 microg/liter or less. Subjects were separated based on BMI and GH testing into three groups: normal weight, obese GH sufficient (GHS), and obese relative GH deficient (GHD). Age, gender, and race were similar between the groups. BMI, percentage body fat, and visceral adiposity did not differ between obese GHS and relative GHD. RESULTS: Peak GH was associated with cIMT, IGF-I, high-density lipoprotein, low-density lipoprotein, triglycerides, adiponectin, C-reactive protein, and TNF-alpha (all P < 0.05). Obese GHS subjects had similar cIMT compared to normal-weight subjects (P = not significant), whereas obese GHD subjects had higher cIMT compared to normal-weight subjects (P < 0.05) (normal weight, 0.645 +/- 0.023, vs. obese GHS, 0.719 +/- 0.021, vs. obese GHD, 0.795 +/- 0.063 mm; P = 0.01 by ANOVA). Similar results were seen in sensitivity analyses with less stringent cutoffs (< 5, < or = 8, < 9 microg/liter) to define GHD. In multivariate modeling, peak GH remained significantly associated with cIMT after controlling for age, gender, race, tobacco, blood pressure, cholesterol, and fasting glucose (R(2) for model, 0.35; P < 0.0001). CONCLUSIONS: These results suggest that reduced GH secretion is associated with a more abnormal metabolic phenotype in obesity, characterized by increased cIMT, dyslipidemia, insulin resistance, and inflammation.

Effects of obesity, body composition, and adiponectin on carotid intima-media thickness in healthy women.

CONTEXT: Increased common carotid intima-media thickness (IMT) is predictive of coronary artery disease and stroke. OBJECTIVE: In this study, we investigated common carotid IMT by obesity category in a cohort of healthy women without previously known cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: One hundred healthy women (aged 24-59 yr) from the general community enrolled in an observational study conducted at an academic medical center participated in the study. B-mode ultrasound imaging of the common carotid arteries was used to measure common carotid IMT in 99 subjects. Fat distribution was determined by computed tomography. Hormonal and inflammatory parameters related to cardiovascular disease and obesity were measured. RESULTS: IMT was higher in obese [body mass index (BMI) >or= 30 kg/m(2)], compared with overweight women (BMI >or= 25 and < 30 kg/m(2)) [0.69 mm, interquartile range (IQR) 0.60-0.75 mm] vs. 0.62 mm [IQR 0.56-0.68 mm), P = 0.044] and in comparison with lean women (BMI < 25 kg/m(2)) [0.69 mm (IQR 0.60-0.75 mm) vs. 0.59 mm (IQR 0.54-0.67 mm), P = 0.016]. In multivariate modeling, age (beta = 0.0050 mm change in IMT per year of age, P = 0.003), smoking (beta = 0.0044 mm change in IMT per pack-year, P = 0.046), and sc abdominal adiposity (beta = 0.00026 mm change in IMT per square centimeter, P = 0.010) were positively associated with IMT, whereas adiponectin (beta = -0.0042 mm change in IMT per milligram per liter, P = 0.045) was negatively associated with IMT. Visceral adiposity (beta = 0.00048 mm change in IMT per square centimeter, P = 0.092) was not significantly associated with IMT after adjusting for age, race, smoking, sc abdominal adiposity, and adiponectin. CONCLUSIONS: Obesity is associated with increased common carotid IMT in young and middle-aged women. Adiponectin and sc abdominal adiposity are associated with carotid IMT in this population.